The electric potential across the mitochondrial membrane is thought to play a role in capturing energy during oxidative metabolism. Despite the general acceptance of this view, the evidence supporting the presence of a significant membrane potential is questionable. To test this theory, we have developed techniques in which microelectrodes are used to measure membrane potentials across the membrane of giant liver mitochondria. The large mitochondria are produced by feeding the mice cuprizone. We would like to test this hypothesis further using two additional approaches. Electrofluorochrometric dyes have been shown to estimate membrane potentials in other systems. The fluorescence of the dyes varies with variations in membrane potential. In addition, changes in metabolic state reflected in changes in membrane potential should have predictable effects on the unidirectional flux of ions. For example, the inhibition of a membrane potential, negative inside should decrease the influx of a cation and increase its efflux. The mechanism of coupling oxidation to phosphorylation and of active transport of ions is fundamental to the understanding of aerobic metabolism. Hence it has far reaching implications in our understanding of metabolic diseases and the functioning of normal and abnormal cells.